Journal Article

Endogenous Neurotrophins and Trk Signaling in Diffuse Large B Cell Lymphoma Cell Lines Are Involved in Sensitivity to Rituximab-Induced Apoptosis

Dubanet, Lydie, Fauchais, Anne-Laure, Lise, Marie-Claude, Jauberteau, Marie-Odile, Troutaud, Danielle, Bordessoule, Dominique, Bellanger, Cynthia

2011

Overview

Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Immunochemotherapy, a combination of rituximab to standard chemotherapy, has resulted in improved survival. However a substantial proportion of patients still fail to reach sustained remission. We have previously demonstrated that autocrine brain-derived neurotrophic factor (BDNF) production plays a function in human B cell survival, at least partly via sortilin expression. As neurotrophin receptor (Trks) signaling involved activation of survival pathways that are inhibited by rituximab, we speculated that neurotrophins may provide additional support for tumour cell survival and therapeutic resistance in DLBCL. In the present study, we used two DLBCL cell lines, SUDHL4 and SUDHL6, known to be respectively less and more sensitive to rituximab. We found by RT-PCR, western blotting, cytometry and confocal microscopy that both cell lines expressed, in normal culture conditions, BDNF and to a lesser extent NGF, as well as truncated TrkB and p75(NTR)/sortilin death neurotrophin receptors. Furthermore, BDNF secretion was detected in cell supernatants. NGF and BDNF production and Trk receptor expression, including TrkA, are regulated by apoptotic conditions (serum deprivation or rituximab exposure). Indeed, we show for the first time that rituximab exposure of DLBCL cell lines induces NGF secretion and that differences in rituximab sensitivity are associated with differential expression patterns of neurotrophins and their receptors (TrkA). Finally, these cells are sensitive to the Trk-inhibitor, K252a, as shown by the induction of apoptosis. Furthermore, K252a exhibits additive cytotoxic effects with rituximab. Collectively, these data strongly suggest that a neurotrophin axis, such NGF/TrkA pathway, may contribute to malignant cell survival and rituximab resistance in DLBCL.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibodies, Monoclonal, Murine-Derived / Antibodies, Monoclonal, Murine-Derived - therapeutic use / Antineoplastic Agents / Antineoplastic Agents - therapeutic use / Apoptosis / Autocrine signalling / B cells / B-cell lymphoma / Biology / Biotechnology / Blotting, Western / Brain / Brain-Derived Neurotrophic Factor / Brain-Derived Neurotrophic Factor - genetics / Brain-Derived Neurotrophic Factor - metabolism / Cancer therapies / Cell culture / Cell survival / Cellular Biology / Chemotherapy / Colorectal cancer / Confocal microscopy / Cytometry / Cytotoxicity / Deprivation / Drug Resistance, Neoplasm / Enzyme-Linked Immunosorbent Assay / Exposure / Flow Cytometry / Fluorescent Antibody Technique / Health aspects / Humans / Immunoenzyme Techniques / Immunotherapy / Kinases / Life Sciences / Lymphocytes B / Lymphoma / Lymphoma, B-Cell / Lymphoma, B-Cell - drug therapy / Lymphoma, B-Cell - metabolism / Lymphoma, Large B-Cell, Diffuse / Lymphoma, Large B-Cell, Diffuse - drug therapy / Lymphoma, Large B-Cell, Diffuse - metabolism / Lymphomas / Malignancy / Medicine / Microscopy / Monoclonal antibodies / Nerve Growth Factor / Nerve Growth Factor - metabolism / Nerve Growth Factors / Nerve Growth Factors - genetics / Nerve Growth Factors - metabolism / Nervous system / Neurotrophic factors / Neurotrophin receptors / Neurotrophins / Polymerase chain reaction / Proteins / Real-Time Polymerase Chain Reaction / Receptor, Nerve Growth Factor / Receptor, Nerve Growth Factor - genetics / Receptor, Nerve Growth Factor - metabolism / Receptor, trkA / Receptor, trkA - genetics / Receptor, trkA - metabolism / Receptor, trkB / Receptor, trkB - genetics / Receptor, trkB - metabolism / Receptor, trkC / Receptor, trkC - genetics / Receptor, trkC - metabolism / Receptors / Remission / Rituximab / RNA, Messenger / RNA, Messenger - genetics / Sensitivity / Signal transduction / Survival / Systems development / Targeted cancer therapy / Tumor cell lines / Tumor Cells, Cultured / Tumor necrosis factor-TNF / Tumors / Western blotting